Nebulized macrophage membrane-engineered triptolide liposomes for Siglec-10/CD24-mediated therapeutic targeting in lung cancer

Non-small cell lung cancer (NSCLC) currently stands as the predominant etiological factor underlying lung cancer-related mortality on a global scale. Conventional drug delivery methods are associated with significant toxic side effects, highlighting the necessity to develop novel targeted delivery systems to improve the therapeutic efficacy of lung cancer treatment. Here, we aimed to develop a pulmonary drug delivery system for triptolide (TP) to treat orthotopic lung cancer. Herein, triptolide-loaded liposomes (TP-lip) were prepared to reduce the toxicity and improve the solubility of triptolide. Macrophage membranes (MM), rich in Siglec-10, were engineered onto the liposomes to enhance the tumor targeting through specific binding to Cluster of differentiation 24 (CD24), a molecule overexpressed on lung tumor cells. Regardless of macrophage polarization, the high Siglec-10 expression on cell membranes ensures effective tumor cell targeting. After modifying different types of MMs on TP-lip and nebulizing them, the aerodynamic fine particle fraction (FPF) of TP formulations exceeded 50%, and the mass median aerodynamic diameter (MMAD) was below 5 μm, suitable for pulmonary delivery. MM-modified liposomes showed higher cellular uptake and stronger inhibitory effects on LLC lung tumor cells. Pharmacokinetic studies showed that intratracheal administration (aerosolized drug delivery) of MM-lip could reduce the systemic drug exposure compared to intravenous injection, while achieving effective accumulation in lung tissues. Pulmonary delivery of M0-TP-lip significantly enhanced the anti-tumor efficacy and improved the lifespan of orthotopic lung tumor-bearing mice, with no apparent systemic toxicity observed. Overall, this highlights the potential of inhalable, biomimetic triptolide loaded liposomes for pulmonary tumor treatment through Siglec-10-mediated targeting.